A normal erection occurs as a result of a coordinated vascular event in the penis. This is usually triggered neurally and consists of vasodilation and smooth muscle relaxation in the penis and its supplying arterial vessels. Arterial inflow causes enlargement of the substance of the corpora cavernosa. Venous outflow is trapped by this enlargement, permitting sustained high blood pressures in the penis sufficient to cause and maintain rigidity. Muscles in the perineum also assist in creating and maintaining penile rigidity. Erections are induced centrally in the nervous system by sexual thoughts, fantasy, and/or stimulation and can be reinforced locally by reflex mechanisms (e.g., tactile stimulation).
Impotence or male erectile dysfunction is defined as an inability to achieve and sustain an erection sufficient for satisfactory sexual performance and intercourse. Impotence in any given case can result from psychological disturbances (psychogenic), from physiological abnormalities in general (organic), from neurological disturbances (neurogenic), hormonal deficiencies (endocrine) or from a combination of the foregoing.
As used herein, psychogenic impotence is defined as functional impotence with no apparent overwhelming organic basis. It may be characterized by an ability to have an erection in response to some stimuli (e.g., masturbation, spontaneous nocturnal, spontaneous early morning, video erotica, etc.) but not others (e.g., partner or spousal attention).
Current diagnosis of and professional thinking on the etiology of male erectile dysfunction has focused on the severity of the condition, i.e., mild, moderate and severe. One method of diagnosis employs oral medication as a means to distinguish dysfunctional patients who can respond to oral medications from those who require more direct intervention, i.e., such as intracavernosal injection or surgery.
Oral medicines, are particularly desirable and sought after discreet forms of treatment. See, for example, Leland J., "A Pill for Impotence?", Newsweek, pp. 62-68 (Nov. 17, 1997).
Apomorphine, a selective dopamine receptor agonist, has been widely utilized as an emetic agent, sedative, antiparkinsonian agent and a behavior altering agent and previously was shown to have very poor oral bioavailability. See, for example, Baldessarini et al., in Gessa et al., eds., Apomorphine and Other Dopaminomimetics, Basic Pharmacology, 1, pp. 219-228, Raven Press, N.Y. (1981). However, recent research and clinical studies of the effect of orally administered apomorphine on penile tumescence in male patients afflicted with psychogenic impotence show that oral administration of apomorphine can indeed induce an erection in a psychogenic male patient in response to physical sexual stimulation. The specific mechanisms by which apomorphine acts to produce an erectile response in a human male are not yet completely understood, but are believed to be centrally acting through dopamine receptor stimulation in the medial preoptic area of the brain.
While apomorphine can be orally administered in an effective dose, the dose required to achieve a significant erectile response must not be accompanied by substantial nausea and vomiting, or other undesirable side effects, such as arterial hypotension, flushing and diaphoresis (sweating). At dosages of more than 6 milligrams, for example, in some instances the level of accompanying nausea and vomiting interferes with the benefit in treating male erectile dysfunction with apomorphine.
During normal penile erections, when the inflow of blood to the corpora cavernosa engages the sinusoidal spaces, the trabecular tissue compresses small cavernosal veins against the thick fibrous tissue surrounding the corpora to maintain the erection. To mediate these changes in blood flow, nitric oxide is released from postsynaptic parasympathetic neurons and, to a lesser extent, endothelial cells and .alpha.-adrenergic neurons are inhibited in the arterial and trabecular smooth muscle. Nitric oxide, which is readily diffusible, stimulates the formation of increased cyclic guanosine monophosphate (GMP) in the corpus cavernosum by guanylate cyclase to relax the smooth muscle cells.
Recently, the oral use of the citrate salt of sildenafil has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of male erectile dysfunction. Sildenafil is reported to be a selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5 (PDE5), the predominant isozyme metabolizing cyclic GMP formed in the corpus cavernosum. Since sildenafil is a potent inhibitor of PDE5 in the corpus cavernosum, it is believed to enhance the effect of nitric oxide, thereby increasing cavernosal blood flow in the penis, especially with sexual stimulation. Inasmuch as sildenafil at the currently recommended doses of 25-100 mg has little effect in the absence of sexual stimulation, sildenafil is believed to restore the natural erectile response to sexual stimulation but not cause erections in the absence of such stimulation. See, for example, Goldstein et al., "Oral Sildenafil in the Treatment of Erectile Dysfunction," The New England Journal of Medicine, 338, pp 1397-1404 (1998). The localized mechanism by which cyclic GMP stimulates relaxation of the smooth muscles has not been elucidated.
In dose-response studies, increasing doses of sildenafil (25 to 100 mg) reportedly increased the erectogenic efficacy of sildenafil. However, the oral administration of sildenafil is also accompanied by dose-responsive undesirable side effects. Consequently, at dosages higher than 50 milligrams, the incidence of such side effects as abnormal vision problems ranging from blue or green halo effects to blurring, dyspepsia, nasal congestion, blinding headaches, flushing redness, diarrhea, dizziness, rash, and urinary tract infection increases.
Other more serious side effects have been reported, such as syncope (loss of consciousness), priapism (erection lasting 4 hours or more) and increased cardiac risk (coital coronaries), can be brought on in some cases by physiological predisposition, adverse drug interaction or potentiation, or by drug abuse. In particular, hypotension crisis can result from the combination of sildenafil citrate and organic nitrates, causing, in some cases death, so its administration to patients who are concurrently using organic nitrates (such as nitroglycerin) in any form is contraindicated. Moreover, the long-term effects of large doses of sildenafil containing drugs is not known. See, for example, Handy B., "The Viagra.TM. Craze," Time, pp 50-57 (May 4, 1998).
Some attempts have been made to treat sexual dysfunction in females caused by hysterectomy, menopause and vascular disorders, like diabetes, by employing topical gels containing Viagra.TM.. See, for example, Valdes-Rodriguez, A, "Viagra for her," Chicago Tribune, Womanews Section 13, p 7 (Dec. 20, 1998).
Thus there is an ongoing need and desire for a discreet, convenient treatment of sexual dysfunction in humans, suitable for men or women, and preferably for oral delivery systems without the incidence or likelihood of undesirable attendant side effects.